UCLA collaboration identifies
immune system link to schizophrenia

Disruptions also found in cellular pathways involved in memory and cognition

Mark Wheeler |
July 01, 2009

Schizophrenia is a devastating mental disease, thought to be caused by the interaction of both genetic and environmental factors. Because there is no biochemical test that can identify the disorder, physicians rely upon the recognition of its symptoms — which can include auditory hallucinations and paranoia — in order to make their diagnosis.

Now following on their earlier work that identified three gene locations that may be implicated in schizophrenia, researchers at UCLA and colleagues from around the world have, for the first time, identified additional genes that confirm what scientists have long suspected — that the immune system may play a role in the development of the disorder. Further, they have also identified genetic anomalies that disrupt the cellular pathways involved in brain development, memory and cognition, all markers of schizophrenia.

The research appears in the July 1 online edition of the journal Nature.

Roel Ophoff, the co-lead author and an assistant professor at the Center for Neurobehavioral Genetics at the UCLA Semel Institute for Neuroscience and Human Behavior, and his collaborators from nearly 50 institutions worldwide, performed a genome-wide scan of 2,663 people diagnosed with schizophrenia and 13,498 controls from eight European locations. They were looking for single nucleotide polymorphisms (SNP), genetic variations that are commonly present in the general population but more often present in those suffering from the disorder. In total, nearly 314,000 SNPs were included in their analysis.

They found significant associations with genetic markers on the Major Histocompatibility Complex (MHC), a group of genes that controls several aspects of the immune response. Further, they discovered additional variations in two other genes, called NRGN and TCF4, which points to perturbation of pathways involved in brain development, memory and cognition.

"This is another step forward in understanding the biological basis of this disorder, one that robs people of their lives," said Ophoff, who holds a joint appointment at the University of Utrecht, The Netherlands. "It also shows the importance of worldwide collaborations for the study of schizophrenia genetics, because it allows us to do very large numbers of scans."

The findings are significant yet not without challenge, said Ophoff, since the study aimed at the "common variants" in the human genome. "In other words," he said, "these are not rare mutations present in only a few individuals, but these genetic variants are abundantly present in the population. Anybody could carry this variant, but that doesn't mean they will necessarily develop the disease. Yet, when you look at the population at large, these variants are more often present in patients than in healthy control subjects."

And that’s important, he noted, in developing new techniques to thwart the disease. "Knowing these specific genes are involved in the pathway leading to schizophrenia provides unique clues as to which molecular mechanisms are involved," he said.

While the association between schizophrenia and the immune system has long been suspected, the evidence for it has, until now, been mostly circumstantial. And impaired cognitive and memory functions are increasingly being recognized as core features of schizophrenia, which are poorly addressed by current medications.

"The three common genetic variants we describe, then, which we feel predisposes certain individuals to schizophrenia, have the potential to be translated into targets for the development of new and novel medications," Ophoff said.

Some 40 other authors and institutions contributed to the paper, and there were multiple funding sources; for UCLA, funding was provided by the National Institute of Mental Health. Other UCLA authors included Dr. Nelson Freimer, director of the Center for Neurobehavioral Genetics and professor of psychiatry, and Rita Cantor, professor of human genetics, both members of the DavidGeffenSchool of Medicine. The UCLA authors report no conflicts of interest.

The Semel Institute for Neuroscience and Human Behavior is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders. In addition to conducting fundamental research, the institute faculty seeks to develop effective treatments for neurological and psychiatric disorders, improve access to mental health services and shape national health policy regarding neuropsychiatric disorders.